Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen that rarely causes disease in healthy people, but is a significant problem for critically ill immunocompromised individuals or individuals with defective lung epithelial cell clearance of pathogens, e.g. cystic fibrosis (CF) patients. Infection is a major problem in individuals who have CF, where chronic infection of the lung with P. aeruginosa causes progressive loss of lung function. In CF patients, it is known that the number of P. aeruginosa cells that express the Type III secretion system (TTSS) is a small proportion of the total P. aeruginosa burden in the lungs. This may explain why CF patients can tolerate a high bacterial burden in their lungs for many years. However, the TTSS-expressing cells may play an important role in the slow, progressive loss of lung function that leads to early death due to lung failure. Others at risk from P. aeruginosa infection include patients on mechanical ventilators, neutropenic cancer patients, and burn patients, where infections are acute and most of the P. aeruginosa cells express the TTSS.
Patients at risk for P. aeruginosa infection may also have other bacterial infections, e.g., Staphylococcus aureus (S. aureus) infections. The levels of P. aeruginosa and S. aureus infection within a patient are commonly perceived as being inversely proportional, i.e., when P. aeruginosa levels are high, S. aureus levels are low. In particular, it has been observed that as CF patients acquire P. aeruginosa chronic infection, S. aureus is cultured less frequently from the sputum. Studies have further shown that P. aeruginosa simultaneously suppresses the growth and enhances the amino glycoside resistance of S. aureus by the production of a compound HQNQ (O'Connell, Nature Reviews Microbiology, Vol. 5, February 2007, Hoffman et al., Proc. Natl. Acad. Sci. USA 103:19890-19895, 2006). It is thus commonly believed that treatment regimens that reduce the level of P. aeruginosa provide an opportunity for the S. aureus to grow. It may therefore be detrimental to reduce the level of P. aeruginosa in patients co-infected with S. aureus and P. aeruginosa because it creates an environment in which pathogenic S. aureus strains can increase, causing patient morbidity and mortality.
One of the virulence mechanisms of P. aeruginosa through which cytotoxins are injected into host cells is the type III secretion system (TTSS). The type III secretion system is an important virulence factor in that it inhibits host defense systems and damages epithelial barriers. Upon activation, the type III secretion apparatus translocates toxins into the cytoplasm of the host cell, resulting in cell rounding, lifting, and cell death by necrosis. One method of treating P. aeruginosa infection targets the TTSS, e.g., the V antigen of the P. aeruginosa TTSS, which is referred to as “PcrV”.
Antibodies that target the TTSS have been suggested as therapeutic agents for the treatment of patients with a P. aeruginosa infection. The current invention is based, in part, on the surprising discovery that patients that have a S. aureus infection and are co-infected with P. aeruginosa have reductions in the level of S. aureus when treated with an agent that selectively targets the TTSS of P. aeruginosa. This is counter to the expectation that S. aureus levels would increase if P. aeruginosa levels were reduced.